Brenner and Rector's The Kidney, 8th ed.

CHAPTER 55. Erythropoietin Therapy in Renal Disease and Renal Failure

John C. Stivelman   Steven Fishbane   Allen R. Nissenson

  

 

Treatment of Anemia in Chronic Kidney Disease and End-Stage Renal Disease with Erythropoietin and Iron, 1884

  

 

Historical Evolution of Erythropoietin Isolation; Studies Resulting in the Use of rHuEPO for Human Disease, 1884

  

 

Patient Selection for Treatment, 1884

  

 

Evidence-Based Erythropoietin Treatment, 1885

  

 

Evidence-Based Iron Treatment, 1887

  

 

Evidence-Based Iron Monitoring, 1889

  

 

Evidence-Based Approach to Iron Safety, 1890

  

 

Delayed or Diminished Response to rHuEPO Treatment, 1891

  

 

Iron Deficiency, 1891

  

 

Secondary Hyperparathyroidism, 1891

  

 

Aluminum Toxicity, 1892

  

 

Hemoglobinopathies and Hemolytic Anemia, 1892

  

 

Folate and Vitamin B12 Deficiency, 1892

  

 

Multiple Myeloma, 1892

  

 

Inflammation, 1892

  

 

Carnitine Deficiency, 1892

  

 

Angiotensin-Converting Enzyme Inhibition, 1893

  

 

Effect of Delivered Dialysis Dose and Membrane, 1893

  

 

Anti-rHuEPO Antibodies, 1893

  

 

Individual Patient Marrow Sensitivity to rHuEPO, 1893

  

 

Therapeutic Goals And Benefits: Target Hemoglobin Issues, 1893

  

 

Mortality, 1894

  

 

Hospitalization, 1894

  

 

Brain and Cognitive Function, 1894

  

 

Quality of Life/Exercise Capacity, 1895

  

 

Cardiovascular Disease, 1895

  

 

Kidney Function, 1895

  

 

Blood Rheology/Hemostasis/Oxidative Effects, 1896

  

 

Pharmacoeconomic and End-Stage Renal Disease Program-Related Issues in rHuEPO Treatment, 1896

TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE WITH ERYTHROPOIETIN AND IRON

Historical Evolution of Erythropoietin Isolation; Studies Resulting in the Use of rHuEPO for Human Disease

Anemia was first recognized as a common accompaniment of kidney disease by Richard Bright, who noted in 1836 that “…after a time, the healthy color of the countenance fades” in affected patients.[1] Although the cause of the pale appearance of such patients was unknown, over the subsequent 60 years the notion that decreased blood oxygen tension stimulated RBC production gradually gained acceptance.[2] Considerable debate ensued, however, over the mechanism of hematopoietic stimulation, specifically, whether it was a direct effect or mediated by a hormone.[3] Although factors that stimu-lated erythropoiesis had previously been isolated from the urine and plasma of anemic humans and animals,[2] by the late 1950s, studies by Reissmann,[4] Erslev,[5] and Jacobson and co-workers[6] clearly demonstrated that a putative stimulator of RBC production did indeed exist and was located in the kidney. After studies showing that urine erythropoietin levels correlated inversely with changes in oxygen transport,[7] isolated perfused kidney experiments[8] provided irrefutable evidence of the source of this potent hormone, which was ultimately purified by Miyake and colleagues from the urine of patients with aplastic anemia in 1977.[9] At present, the peritubular capillary endothelial cell and peritubular fibroblast appear to be responsible for its synthesis within the kidney. [10] [11] [12]

The pioneering work of Eschbach and Adamson in the 1970s and 1980s demonstrated that the lack of an adequate quan-tity of erythropoietin is the predominant cause of renal anemia. Initially working with sheep, these investigators demonstrated that erythropoietin-rich plasma infused into normal and uremic sheep induced identical erythropoietic responses.[13] Chronic administration resulted in correction of anemia.[14] Subsequent studies in a hemodialysis patient, who received erythropoietin isolated from a patient with secondary polycythemia, reported a positive reticulocyte and ferrokinetic response, the first to be demonstrated in a uremic human. These studies were followed by isolation of the gene for native erythropoietin by Lin and colleagues [15] [16] in 1985, its cloning in the Chinese hamster ovary cell, and ultimately, the development of rHuEPO in 1986. Positive clinical trials of this agent shortly thereafter by Eschbach and associates reinforced the finding that deficiency of native erythropoietin was the primary cause of the anemia of renal disease and that this deficiency could be reversed by administration of the recombinant form of the protein. [17] [18] The impact of this research cannot be overstated: it is estimated that over 95% of patients in the United States with end-stage renal disease (ESRD) receive replacement therapy with some form of recombinant erythropoietin. Transfusion dependence in ESRD has virtually been eliminated by this therapy,[18] its infectious sequelae thereby reduced, and the quality of life of patients with CKD and ESRD markedly enhanced.

Patient Selection for Treatment

Although prior American,[19] European,[20] and Canadian[21] evidence-based guidelines for management of anemia linked initiation of anemia evaluation to a depressed hemoglobin value (<11 g/dL for premeno-pausal females, <12 g/dL for adult men and postmenopausal women in the U.S. and European guidelines; <11 g/dL for males and postmenopausal women in the Canadian guidelines), [19] [20] [21] recent K/DOQI and European recommendations have suggested higher thresholds of less than 13.5 g/dL in males [22] [23] and either less than 12.0 g/dL[22] or less than 11.5 g/d[23] in adult females. The baseline workup in patients with CKD and anemia before further erythropoietic therapy should include a hemogram with erythrocyte indices, reticulocyte count, transferrin saturation, with either percent hypochromic erythrocytes or reticulocyte hemoglobin content, [22] [23] and serum ferritin. [19] [21] [22] [23] The additional use of C-reactive protein as a baseline screening tool for the presence of underlying inflammation, a potential cause of a poor response, has enjoyed widespread acceptance overseas[23] and is increasingly being used in the United States. Any suggestion of iron deficiency should be followed by studies to exclude occult blood loss. Clinical suspicion of either a primary hematologic disorder or one known to induce a delayed or diminished response (see later) to initial therapy should prompt further evaluation, including careful review of recent clinical medical history,[22] assessment of water-soluble vitamin concentrations, differential leukocyte count, and exclusion of hemolytic states, paraproteinemia, aluminum intoxication, and high-turnover bone disease. [19] [20] [21] [22] Thorough pursuit of any poorly defined ongoing or new illness may unmask an important impediment to effective treatment.

Although the major evidence-based guidelines recommend consideration of hematopoietic treatment for patients with renal disease and a hemoglobin concentration of less than 11 to 13 g/dL, such guidelines beg the broader, unresolved physiologic issue of whether treatment should in fact begin before anemia evolves [22] [24] in order to limit patient vulnerability to the potential end-organ sequelae of prolonged anemia in the predialysis period[25] (also discussed at length later in the section on Therapeutic Goals and Benefits: Target Hemoglobin Issues). Even given optimal patient eligibility for treatment, however, early inception of care before initiation of renal replacement therapy depends critically on its accessibility, which within the United States remains complicated by regulatory issues related to reimbursement for home versus on-site treatment, and on geographic variation in hemoglobin levels at which payment for rHuEPO is authorized (see the later section on Pharmacoeconomic Issues in Treatment).

Evidence-Based Erythropoietin Treatment

rHuEPO and Darbepoetin Alfa

Several forms of rHuEPO are available for the treatment of patients with anemia related to chronic renal failure, ESRD, and other nonrenal disorders by either the intravenous or subcutaneous route. Epoetin alfa and beta (165 amino acids)[26] are glycoproteins produced through recombination of the human erythropoietin gene with the Chinese hamster ovary cell. [15] [16] These rHuEPO molecules differ modestly in that the beta form contains quantitatively more basic sialic acid residues, which may confer slightly higher in vivo/in vitro activity.[27] The half-time (t½) of epoetin alfa is between 4 and 12 hours when administered intravenously and is prolonged to approximately 25 hours by subcutaneous injection. [28] [29] Comparative pharmacokinetic studies in normal males have demonstrated that the beta form has a slightly larger volume of distribution, a 20% longer terminal elimination t½ after intravenous administration, and delayed subcutaneous absorption when compared with the alfa form,[30] although these differences do not appear to be reflected in any substantive difference in clinical efficacy.[27] A third rHuEPO molecule, omega, produced in baby hamster kidney cells, has become available for clinical trials and possesses slightly different glycosylation and hydrophilicity characteristics. [31] [32] A fourth, epoetin delta, an agent produced by human cells engineered to transcribe and translate this gene under control of a newly introduced regulatory sequence, is under-going human trials at present.[33] Finally, a pegylated form of erythropoietic stimulating agent, Continuous Erythro-poietin Receptor Stimulator, has concluded clinical trials and is being considered for approval by the Food and Drug Administration (S. Fishbane, personal communication, August 2006).

Further investigation into the biologic properties of native human erythropoietin and rHuEPO has revealed a direct relationship between its in vivo activity, t½, and sialic acid carbohydrate content. Affinity for receptor binding varies inversely with this specific carbohydrate content.[34] Such properties suggested a mechanism for enhancing both the duration of action and the biologic efficacy of this hormone inasmuch as increased glycosylation is postulated to slow metabolic clearance.[35] To this end, in the late 1990s a hyperglycosylated rHuEPO analog with five N-linked carbohydrate chains (rHuEPO contains three), designated darbepoetin alfa (also “novel erythropoiesis-stimulating protein,” or NESP), was synthesized and, now approved, sees extensive use in humans. [36] [37] [38] [39] In a double-blind randomized crossover study of peritoneal dialysis patients, Macdougall and colleagues[36] showed dramatic prolongation of the mean t½ for intravenous darbepoetin when compared with intravenous rHuEPO (25.3 versus 8.5 hours) despite comparable volumes of distribution (52.4 versus 47.8 mL/kg). In six patients in whom darbepoetin was administered subcutaneously, the mean terminal elimination t½ increased to 48.8 hours. Despite these properties, darbepoetin and rHuEPO are identical with respect to their effect on intracellular signaling and mechanism of action, and they appear to have the same efficacy whether administered subcutaneously or intravenously. [40] [41]

In the past several years, a variety of safety and efficacy trials investigating the use of darbepoetin have addressed correction of anemia at varying doses, routes, and frequency of administration in predialysis, peritoneal dialysis, and hemodialysis patients; maintenance of stable hemoglobin concentrations in the setting of conversion from rHuEPO to darbepoetin therapy at a decreased dosing frequency; and long-term maintenance of hemoglobin levels. [36] [37] [38] [39] [40] [41] [42] [43] [44] Taken together, these studies suggest that the initial dose of darbepoetin should be 0.45 to 0.75U/kg, that therapy can be switched from twice to three times weekly or weekly rHuEPO administration to weekly or even alternate-week darbepoetin with successful maintenance of hemoglobin levels, and that darbepoetin is equally effective as rHuEPO in maintaining hemoglobin levels in dialysis patients with less frequent dosing. Recent reports suggest that even once monthly dosing may maintain hemoglobin more than 10 gm in patients previously treated every 2 or 3 weeks,[45] although others have noted that similar regimens may not have prolonged efficacy.[43] The side effect profile of darbepoetin therapy is comparable to that of rHuEPO, and no antibody formation has been noted.[42]

Dose, Route of Administration, Titration, and Monitoring

Since human trials with rHuEPO began in 1985 a large body of literature has evolved in which a wide spectrum of safe, effective treatment strategies have been described. Organization and evaluation of these studies have been enhanced by the coincident growth of evidence-based medical practice in nephrology, as exemplified by the American, European, and Canadian evidence-based practice guidelines [19] [20] [21] [22] [23] for the management of anemia in renal disease. These efforts have helped refine effective dosing and monitoring of rHuEPO therapy.

A variety of regimens are effective in raising hemoglobin to target levels (see section on Therapeutic Goals and Benefits: Target Hemoglobin Issues), the route of delivery of which may vary according to the clinical setting and the modality of renal replacement therapy. Patients with CKD and those undergoing peritoneal dialysis almost uniformly receive rHuEPO or darbepoetin by subcutaneous injection; hemodialysis patients may receive treatment by subcutaneous injection or intravenous infusion. Assuming adequate iron stores, prior overviews of available evidence-based guidelines suggested comparable initiating doses of rHuEPO (80 to 120U/kg/wk subcutaneously, 120 to 180U/kg/wk intravenously per K/DOQI,[19] 50 to 150U/kg/wk subcutaneously or intravenously per European best-practice guidelines,[20] and 100 to 200U/kg/wk per Canadian guidelines[21]), delivered as doses divided twice or three times per week. Once-weekly dosing of rHuEPO by the subcutaneous route [19] [40] (but less so by the intravenous route[40]) has been supportable with the present available evidence. The primary treatment regimen in the United States, three-times-weekly intravenous administration to hemodialysis patients at the doses noted earlier, is at present effective, but as might be inferred from the differences in t½ between the subcutaneous and intravenous routes, far less efficient use of rHuEPO is achieved with this regimen (among 36 studies involving 2028 patients, the rHuEPO dose needed to maintain a hematocrit of 33% varied between 0% and 68% lower than that required intravenously).[19] The reasons for the widespread preference for this route of administration may relate in large part to use of the intravenous route in the initial trials to optimize response, to greater patient acceptance of this route of administration, and secondarily, to pharmacoeconomic issues in hormone utilization (see later section on Pharmacoeconomic and ESRD Program-Related Issues in rHuEPO Treatment). Successful darbepoetin therapy has been achieved with both subcutaneous and intravenous routes at the dose range noted previously, and it maintains target hemoglobin levels at frequencies of once-weekly every-other-week, or every third week administration. [41] [42] [45]Intraperitoneal administration in peritoneal dialysis patients has been examined for those who cannot tolerate either subcutaneous or intravenous administration; such administration requires a dry abdomen or the presence of minimal dialysate for optimal absorption,[19] and the risk of peritonitis may be increased, particularly in children receiving therapy by this route.[46]

Given the nearly uniform efficacy of treatment by virtually all routes and frequencies of administration, current treatment strategies have de-emphasized specific prescriptive approaches to frequency, interval, rate, and routes of administration and have instead favored overall matching of dose, frequency, and route of administration with their appropriateness for each patient, that patient's modality of renal replacement therapy, CKD or ESRD status, and clinical condition. [22] [23]

Suggested safe rates of hemoglobin correction range from 1 to 2 g/dL/mo and should be less than 2.0 to 3.0 g/dL/mo. [19] [20] [21] [22] Concern has been raised regarding blood pressure control with more rapid rates of correction,[18]potential induction of access clotting, and prolonged oscillation of hemoglobin values around the desired target causing a delay in attaining stable levels.[19] Patients with a slow initial response over the first month of treatment may have rHuEPO increased by up to 25% to 50%. [19] [20] [21] [22] [23] A dose reduction of 25% or extension of the interval between doses is reasonable titration for patients experiencing rapid increases in hemoglobin. A stable hemoglobin concentration occurs when the rate of rHuEPO-generated erythrocyte entry into the circulation equals the rate of exit of these cells from the circulation at senescence. Thus, frequent changes in dose and, in particular, discontinuation of treatment, which results in cessation of erythrocyte entry at rHuEPO-stimulated rates while egress at that rate continues, may cause wide fluctuations in response to therapy, especially when administration of rHuEPO is started and stopped repetitively. [19] [22] [47] [48] Of note, the frequency of dose adjustment in the setting of biweekly hemoglobin testing does not appear affected by whether short or long-acting agents are used.[39]

The frequency of monitoring rHuEPO therapy, particularly in the United States, has reflected a fusion of rational practices and permissible reimbursement for performance of laboratory evaluations. After treatment has begun, provided that iron stores and essential cofactors are either adequate or being replenished, hemoglobin should be checked as often as biweekly. [19] [20] [22] [23] After a stable hemoglobin concentration is attained, it should be checked at least monthly, with follow-up at shorter intervals (biweekly) for dosage changes, [19] [20] [21] [22] [23] or changes in clinical status such as intercurrent illnesses, or hospitalization. Iron stores, measured by transferrin saturation and ferritin, should be evaluated monthly during initial treatment,[22] and at least every 3 months during stable erythropoietin treatment, with evaluations timed appropriately around periods of iron repletion [19] [49] to avoid artifactually elevated values. More frequent evaluation of iron stores is reasonable but may also be limited by reimbursement allowances.

Potential Adverse Effects of Treatment

At the time of release of rHuEPO for use in CKD and ESRD patients, many expressed concern regarding the development of a variety of serious potential complications of therapy, including worsening hypertension (occasionally in accelerated form), seizures, impaired solute clearance (particularly potassium), and an increased frequency of thrombotic events at (but not confined to) vascular access sites. Due attention has been devoted to all these concerns, and few have materialized over time as major clinical issues in the routine use of rHuEPO.

Changes in blood pressure regulation, either de novo hypertension or increasing antihypertensive medication requirements, are a frequent concomitant of treatment that occurred in an estimated 23% of patients in the largest meta-analysis.[19] Although a rising erythrocyte mass resulting in an increase in peripheral resistance not matched by a comparable decrease in cardiac output has been suggested to reverse the anemia-induced vasodilation in hemodialysis patients,[50] its role as the primary contributor to this phenomenon has been questioned. [51] [52] Several mechanisms, taken together, may play a role in increasing vascular reactivity in the setting of rHuEPO treatment, including a diminished effect of nitric oxide (diminished synthesis or resistance), release of endothelin and vasoconstrictor prostanoids,[20] elevation of cytosolic free calcium in smooth muscle cells, [51] [52] and a trophic effect of rHuEPO on endothelial cell growth.[51] Discrete roles for sensitivity to catecholamines or involvement of the renin-angiotensin system appear less probable.[51]

Worsening blood pressure control in patients undergoing therapy should be managed with a reduction in extracellular fluid volume (assuming that hemoglobin is not seriously out of the target range), initiation or an increase in anti-hypertensive medications, or in rare instances, a decrease in rHuEPO dose. The risk of precipitating seizures in patients being treated with rHuEPO, apart from that associated with hypertensive encephalopathy, has not appeared to be increased with appropriate attention to dosing and titration guidelines, and a previous history of seizures should not preclude treatment with rHuEPO.[19]

Initial concerns at the time of rHuEPO's introduction that increases in red cell mass, changes in blood rheology, and the use of high-efficiency/flux dialyzers with short dialysis times might result in worsening azotemia and hyperkalemia [17] [53] [54] [55] have not materialized as clinically significant issues. The incidence of reported hyperkalemia, in particular, has been minimal, with only 12 episodes in 1167 patients noted by the K/DOQI in 1997.[56]Although decrements in solute clearance have been reported with successful treatment, [53] [54] [57] they are small (10% to 15%), and when the delivered dialysis dose is closely monitored, shortfalls in delivered Kt/V can be investigated and rectified prospectively.[58]

Additional concern has centered on the relationship between rHuEPO treatment and enhanced thrombotic tendencies, particularly in vascular access sites. Although both platelet and endothelial function improve as hemoglobin increases in response to rHuEPO,[20] reviews of 26 studies involving over 4000 rHuEPO-treated patients with mean hematocrit values of 34% (targets less than 36%) have revealed an average clotting incidence of only 7.5%. [19] [20]Few controlled studies exist, and at present, there does not appear to be any added risk of thrombosis in rHuEPO-treated patients with either grafts or fistulas, save possibly in those with higher hemoglobin concentrations (>12.0 g/dL; see discussion of normalization of hemoglobin, later). Data from the U.S. normalization of hematocrit trial demonstrate a higher rate of both fistula and graft thrombosis in patients randomized to the higher hemoglobin group (hemoglobin, 13 g/dL), although no correlation between the hemoglobin concentration attained, rHuEPO dose, and access thrombosis was observed[59]; of note, however, is the fact that the overall thrombosis rate in both groups was elevated when compared with the European experience.[20] At present, no consistent findings demonstrate a clear advantage to one or another form of antiplatelet therapy in maintaining access patency in patients receiving rHuEPO, and as yet no studies have been performed to address this issue in patients with a normalized hemoglobin concentration.

Although certainly within the repertoire of potential adverse sequelae of rHuEPO treatment, these complications have proven modest—perhaps even minimal—barriers to effective treatment, and should not be regarded as contraindications to use of the agent, or reasons to withhold it.[22] Development of such clinical issues during the course of therapy obligates their appropriate treatment, and there is there is no evidence that curtailing therapy with rHuEPO improves their outcome.[22]

Evidence-Based Iron Treatment

Oral Iron

Erythropoietin therapy is most successful when adequate iron stores are present.[60] To achieve this goal in patients with kidney disease, therapeutic iron supplementation is often necessary by either the oral or parenteral route. Oral supplementation of iron offers the benefits of simplicity, low cost, and safety, but its efficacy in hemodialysis patients is limited. K/DOQI guidelines recommend that when oral iron is used in adults, 200 mg of elemental iron should be administered daily in two to three divided doses.[19]

A variety of different oral iron drugs are available ( Table 55-1 ). Most are iron salts, the most widely used being ferrous sulfate. All these agents cause gastrointestinal side effects, including dyspepsia, constipation, and bloating,[61]and little evidence is available to differentiate between them on the basis of efficacy or tolerability. A newer agent, heme iron polypeptide, appears in preliminary studies to have reasonable efficacy and improved tolerability compared with iron salts.[62]

TABLE 55-1   -- Oral Iron Supplements

Iron Supplement

Tablet Size (mg)

Amount of Elemental Iron (mg)

Average Monthly Wholesale Cost (200 mg/day)

Ferrous gluconate

325

35

$5.08

Ferrous sulfate

325

65

$2.29

Ferrous fumarate

325

108

$1.63

Polysaccharide-iron complex

150

150

$7.12

Adapted from National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis 37(suppl 1):182–238, 2001.

 

 

 

The efficacy of oral iron in patients with kidney disease has been rigorously studied only in the subset of patients treated by hemodialysis, and the results have been disappointing in this population. Macdougall and colleagues performed a randomized controlled trial of 37 hemodialysis patients at the initiation of rHuEPO therapy. In this study the efficacy of oral iron was not significantly different from no iron treatment.[63] Similarly, Wingard and associates treated 46 hemodialysis patients with oral iron and found that after 6 months, most patients had a hematocrit of less than 30% with declining iron stores.[64] Markowitz and associates performed a double blinded randomized controlled trial in 49 hemodialysis patients and found no significant difference in efficacy between oral iron and placebo.[65] Fudin and associates studied 39 iron-deficient subjects at the initiation of hemodialysis and found no difference in subsequent hemoglobin levels between oral iron therapy and no iron.[66] Taken together, these studies indicate that oral iron does not have demonstrable efficacy for iron supplementation in hemodialysis patients.

The reasons for failure of oral iron treatment in hemodialysis patients are multiple. First, it is generally thought that compliance with oral iron therapy is poor, although published data evaluating this phenomenon are limited. Hyder and colleagues recently reported on a study of oral iron compliance in pregnant women. Compliance (percentage of prescribed capsules that were actually consumed) was only 61% among women taking a daily supplement.[67] One factor having an impact on compliance with these agents is the frequency of gastrointestinal side effects.[61] However, in the study of Hyder and associates, there was little correlation between side effects and compliance.[67] Other factors that impair compliance include the need to take the medication on an empty stomach, the obligatory intake of more than two pills per day with most supplements to achieve adequate elemental iron intake,[68] and incomplete education of the patient regarding the purpose and goals of iron therapy. It should be noted, however, that even in the studies reported earlier in which compliance was generally encouraged and monitored, oral iron efficacy was poor. A second factor explaining the poor efficacy of oral iron is that if oral iron is taken at the same time as food or phosphate binders, there may be interference with iron absorption.[69] In a recent study of the effect of phosphate binders, Pruchnicki and associates found that calcium carbonate, calcium acetate, and sevelamer HCl reduced supplemental iron absorption by 19%, 27%, and 10%, respectively. (The reduction with sevelamer did not reach statistical significance.)[70]

In patients with renal insufficiency who are not yet undergoing dialysis and in those being treated by peritoneal dialysis, ongoing iron losses are far less than what hemodialysis patients experience. Accordingly, iron balance should be easier to attain, and there may be reasonable efficacy for oral iron treatment. However, to date there have been few controlled studies comparing oral iron to either a placebo or no iron control group in these patient populations, so the efficacy of treatment is yet to be established.

The efficacy of oral iron in patients with kidney disease may be enhanced through several simple practices: first, the dose should provide at least 200 mg of elemental iron per day[19] (for ferrous sulfate, this goal would be achieved by taking approximately three 325-mg tablets per day); second, iron administration should occur between meals [71] [72] and should be spaced at least 1 hour apart from the ingestion of phosphate binders, which may also interfere with iron absorption; and third, because iron is absorbed proximally in the gastrointestinal tract, delayed-release iron supplements should be avoided.[73]

Intravenous Iron

Because of the poor efficacy of oral iron supplements when used for hemodialysis patients, intravenous iron is frequently administered. Three such agents are widely available, iron dextran, iron sucrose, and ferric gluconate. The efficacy of intravenous iron has been widely studied in hemodialysis patients, and a substantial body of literature has evolved consistently demonstrating that treatment results in higher hemoglobin levels or a reduced erythropoietin dose requirement, or both. [63] [66] [74] [75] [76] [77] [78] [79] [80] Macdougall and colleagues studied iron treatment in 37 hemodialysis patients with Hgb less than 8.5 g/dL at the initiation of rHuEPO treatment. Subjects were randomized to treatment with no iron, oral iron, or intravenous iron dextran. Patients treated with intravenous iron had a significant increase in mean hemoglobin, from 7.3 ± 0.8 to 11.9 ± 1.2 g/dL. The erythropoietic response to rHuEPO was significantly greater with intravenous iron than with either oral iron or no iron treatment.[63] The magnitude of difference, Hgb 1.9 to 2.0 g/dL lower in patients not treated with intravenous iron, frames the important role of intravenous iron in supporting initial rHuEPO therapy. As the Hgb levels increases, massive quantities of iron are shifted from storage tissues to the erythron, requiring sufficient supplemental iron to support maintenance of iron balance and successful erythropoiesis. In contrast to Macdougall's study at the initiation of rHuEPO treatment, Fishbane and colleagues studied 46 hemodialysis patients during stable rHuEPO therapy. Patients were randomized to 4 months of treatment with either oral iron or iron dextran 200 mg per week. At study conclusion, patients treated with intravenous iron had a higher mean Hct (34.4% versus 31.8%) and a statistically significant 46% reduction in rHuEPO dose requirements.[74] Besarab and colleagues extended the findings of these reports by studying the spectrum of response to intravenous iron. Forty two hemodialysis patients treated with rHuEPO were randomized to intravenous iron targeted to achieve transferrin saturation of 20% to 30% or 30% to 50%. At study conclusion, rHuEPO dose requirements were decreased by 40% among patients randomized to the higher transferrin target, although dose requirements for iron dextran nearly tripled.[79]

Two strategies for administering intravenous iron to hemodialysis patients are in common use. The first entails periodic surveillance for the presence of iron deficiency and, if detected, treatment with a short, repletive course of intravenous iron. Typically 1000 mg can be given in divided doses over a period of 2 to 3 weeks. Patients will generally demonstrate a significant improvement in responsiveness to rHuEPO thereafter. Many, however, will remain iron deficient,[78] so assessment of iron stores should be repeated after completing such a course of treatment. A second strategy is to anticipate iron deficiency by administering small weekly doses to maintain stable iron stores. Weekly doses of 12.5 to 100 mg of intravenous iron may improve responsiveness to rHuEPO. The potential advantage of such an approach lies in linking iron replacement temporally with ongoing iron losses. Assessment of iron stores should be performed at least quarterly, however, to ensure the adequacy of this approach. It is unclear whether these two treatment approaches have any important differences in safety or efficacy; few published studies have compared these strategies, and those reported have had conflicting results. [81] [82]

In patients being treated by peritoneal dialysis or those with CKD who are not yet undergoing dialysis, iron deficiency develops less frequently than in hemodialysis patients because the former patients do not sustain the chronic ongoing losses of iron experienced by those on hemodialysis. [83] [84] Iron still plays a central role in the maintenance of responsiveness to rHuEPO,[85] however, and deficiency states refractory to oral iron replacement develop not infrequently during the course of treatment.[86] When these patients become iron deficient, a course of oral iron should be attempted. If it is not successful in repleting iron stores, intravenous iron can be administered. This treatment may be inconvenient, however, because of the need to establish frequent intravenous access. Several recent studies have compared oral to intravenous iron treatment in patients with CKD, with mixed results. [87] [88] [89] [90] The largest, reported by Van Wyck and associates, randomized 188 subjects with non-dialysis dependent CKD to treatment with oral ferrous sulfate 325 mg thrice daily or intravenous iron sucrose 1000 over 14 days (either two infusions of 500 mg or five infusions of 200 mg). After 8 weeks of follow-up the mean Hgb increased to a slightly greater degree in the intravenous iron group (0.7 mg/dL versus 0.4 mg/dL, p = 0.03). This modest benefit should be weighed against the inconvenience of treatment and the fact that two patients in the intravenous iron group experienced hypotension (one considered serious).[90] Of particular interest was a recent report from Macdougall and colleagues, who tested a rapid 2-minute push injection of iron sucrose in patients with CKD.[91] The injections were generally well tolerated; however, several patients experienced anaphylactoid reactions. Although this was a relatively rare occurrence, it is likely that many physicians would be uncomfortable managing reactions of this type in the office setting.

Several forms of intravenous iron are available, three of which are most commonly used: iron dextran, iron sucrose, and ferric gluconate. Because each has different attributes, they will be discussed separately. Iron dextran has been used for several decades. Its structure is analogous to that of the storage protein ferritin, with both having a dense core of iron oxyhydroxide surrounded by a stabilizing shell.[60] In iron dextran, the shell is composed of dextran chains consisting of variably sized glucose polymers. Although iron dextran is clearly effective, it is associated with risk for anaphylactoid reactions. These reactions are believed to be related to the drug's dextran component because non-iron-containing dextrans, when used as volume expanders, have been associated with similar reaction rates. [92] [93] The mechanism of iron dextran-related anaphylaxis is incompletely understood but may be due to direct release of vasoactive mediators by mast cells.[94] One approach that has been used successfully to block dextran-induced anaphylaxis is hapten inhibition with smaller dextran molecules.[95]

The rate of anaphylactoid reactions with iron dextran was estimated by a recent meta-analysis that found severe adverse reactions occur in approximately 0.6% of patients treated.[96] Moreover, it has been estimated that 31 deaths from iron dextran-related anaphylaxis occurred in the United States between 1976 and 1996.[97] Importantly, Walters and Van Wyck have recently reported that few such reactions occur after the initial doses of iron dextran, so for patients who have repeatedly tolerated treatment there may be no reason to switch to a nondextran form of iron.[98]

Ferric gluconate and iron sucrose are nondextran forms of intravenous iron that appear to be safer than iron dextran.[99] Rather than possessing a dense core of iron hydroxide, such as iron dextran does, these agents have polynuclear iron centers. The cores are surrounded by carbohydrate, primarily sucrose and gluconate (a salt of crystalline gluconic acid) for iron sucrose and ferric gluconate, respectively. Because these agents do not contain a dextran moiety, they appear to have a lower risk of anaphylactoid reactions than iron dextran. Michael and colleagues recently studied over 2500 hemodialysis patients and reported that after single-dose exposure to ferric gluconate, no statistically significant difference could be found in the rate of serious adverse reactions when compared with placebo. Moreover, the rate of such reactions was substantially reduced in comparison with an iron dextran historical control group.[96] A similarly improved safety profile exists for intravenous iron sucrose.[100]

Evidence-Based Iron Monitoring

The K/DOQI anemia guidelines recommend that during the initiation of rHuEPO treatment, iron status be tested every month in patients not receiving ongoing iron repletion. Once rHuEPO dosing and iron maintenance have stabilized, the guidelines recommend monitoring at least every 3 months. [19] [22] Iron assessment in patients with kidney disease has most frequently been performed with two tests, serum ferritin and transferrin saturation. Two other laboratory evaluations, the percentage of hypochromic red cells (PHR) and the reticulocyte hemoglobin content (CHr), may in fact offer greater overall utility.

Serum ferritin is an indirect measure of storage iron and has been thought to reflect iron deficiency in hemodialysis patients when its concentration is less than 100ng/mL. [19] [22] The diagnostic value of serum ferritin, however, is limited by its behavior as a potent acute-phase reactant. [101] [102] Clinical settings may arise in which ferritin values may be quite high even in the presence of iron deficiency, such as in hemodialysis patients, in whom the test probably has a sensitivity of only 41% to 54%. [103] [104] Because of the extraordinarily high rate of false negative results, iron deficiency in hemodialysis patients cannot be excluded by serum ferritin more than 100ng/ml.

Percent transferrin saturation (TSAT) assesses the availability of circulating iron, calculated as TSAT = (serum iron/total iron-binding capacity) × 100. K/DOQI guidelines recommend using a value of less than 20% as an indicator of iron deficiency in patients with kidney disease. [19] [22] This test, though reasonably sensitive, has a specificity in hemodialysis patients of only 61% to 63%. [103] [104] As a result, low values of transferrin saturation may often be falsely positive for the diagnosis of iron deficiency. Because of the poor specificity of transferrin saturation and sensitivity of serum ferritin, it is not surprising that concurrently measured specimens often paradoxically suggest iron deficiency by transferrin saturation and iron overload by serum ferritin (such discordant results are frequently due to the effects of inflammation [105] [106] or functional iron deficiency).[60] Both tests are further limited by their great variability. In one study, the coefficient of variation for both tests was found to be greater than 30%.[107] These limitations in the predictive value of serum ferritin and transferrin saturation mandate that the results of these tests not be used reflexively in guiding iron treatment, but that clinical judgment be used to correlate the results with the patient's clinical status.

Percentage of hypochromic red cells has been found to be a useful measure of iron status in patients undergoing hemodialysis.[108] Tessitore and co-workers found that the test had the greatest utility of any test for the diagnosis of iron deficiency in hemodialysis patients. When the PHR was over 6%, its efficiency was 89.6%, indicating excellent discriminative ability.[109] The test has one important limitation: it is affected by changes in erythrocyte mean corpuscular volume (MCV). When samples are stored or shipped, the MCV may be significantly altered.[110] In the United States, most laboratory samples for hemodialysis patients are shipped to central locations, a factor that might explain the inconsistent results of PHR in several studies [111] [112] and potentially limit its usefulness.

Reticulocyte hemoglobin content (CHr) is a direct measure of iron status at the level of the reticulocyte. Because it is a measure of content instead of concentration, it is unaffected by changes in cell volume. In addition, because reticulocytes circulate for only approximately 24 hours,[113] test results can indicate very acute changes in iron status. Studies have generally found that the test is an accurate measure of iron status in hemodialysis patients. [109] [111] [112] [114] Recently, Fishbane and colleagues found CHr to be a more cost-effective guide to iron management than serum ferritin and transferrin saturation. Importantly, the test was found to have far less variability than noted with other iron monitoring tests.[107] Generally, a CHr value of less than 29 to 31pg indicates a need for more intensive iron treatment.

Targets to Guide Iron Treatment

Evaluation of Iron Storage-Serum Ferritin

Target levels of iron tests have been studied by a variety of methodologies. These have included bone marrow studies, [104] [115] functional studies of response to intravenous iron,[103] nonrandomized trials,[116] and randomized controlled trials.[107] Most studies have demonstrated that the previous K/DOQI target for serum ferritin, 100ng/mL, greatly underestimated the presence of iron deficiency in hemodialysispatients. [74] [103] [104] [109] [112] [114] [115] [117] Two recent randomized controlled trials have provided additional evidence for the need to increase the serum ferritin target. Besarab and co-workers randomized 42 hemodialysis patients to treatment with intravenous iron to maintain transferrin saturation 20% to 30% or 30% to 50%. At study conclusion the subjects in the lower transferrin saturation group achieved a mean serum ferritin of 297ng/ml; those in the higher group had mean serum ferritin of 730ng/ml. The result was a mean 40% reduction in rHuEPO dose for patients in the higher compared to the lower target group.[79] DeVita and colleagues randomized 36 hemodialysis patients to intravenous iron treatment with serum ferritin target levels of 200ng/ml or 400ng/ml (achieved 299ng/mL and 469ng/mL, respectively).[80] With the higher serum ferritin target the final rHuEPO dose requirements were 28% lower than in the low ferritin group.[80]Based on such studies, the most recent K/DOQI guidelines recently have recommended that serum ferritin should be maintained greater than 200ng/mL for hemodialysis patients.[22] For patients with CKD not yet on dialysis or those on peritoneal dialysis, there is far less published evidence related to iron treatment targets. The K/DOQI guidelines recommend maintaining serum ferritin greater than 100ng/mL in these populations.[22]

Evaluation of Iron Availability—Transferrin Saturation and Reticulocyte Hemoglobin Content (CHr)

The K/DOQI recommended level of transferrin saturation is 20%, for all populations with CKD.[22] This target is based on the moderately reasonable sensitivity and specificity of TSAT at 20%, which in studies has varied 50% to 88% and 63% to 80%, respectively. [74] [103] [104] [109] [112] [114] [115] [117] Reticulocyte hemoglobin content (CHr) has been widely studied, although clinical use has lagged behind serum ferritin and transferrin saturation. The K/DOQI recommendation of CHr 29pg[22] is based on a number of studies indicating excellent accuracy and stability for this test. In a randomized controlled trial of 157 hemodialysis patients, Fishbane and colleagues compared iron management based either on CHr or serum ferritin and transferrin saturation. Among patients randomized to CHr driven treatment, there was a significant reduction in both intravenous iron requirements and the overall cost of anemia treatment.[107] Other studies have found CHr to be quite accurate, at various cutoff levels having sensitivity of 57%, 78%, 78%, 100%, and 100% and specificity of 71%, 80%, 87%, 90%, and 93%. [109] [112] [114] [117] [118] In contrast, Kaneko and colleagues[119] in a randomized controlled trial of 197 hemodialysis patients, found treatment based on transferrin saturation led to a significant reduction in mean rHuEPO dose requirements compared to treatment based on CHr. Percentage hypochromic red cells was not specifically addressed in the K/DOQI guidelines.

Evidence-Based Approach to Iron Safety

The human body is critically dependent on adequate circulating and tissue iron stores to ensure the normal function of a variety of cellular and subcellular processes. Free circulating iron, however, is a potent oxidizing agent toxic to lipid membranes through its catalytic effect on the production of hydroxyl radicals in the presence of hydrogen peroxide and superoxide.[120] To ensure an adequate but safe supply of iron, storage and transport complexes such as ferritin and transferrin sequester it from free circulation in the blood and concentrate it within tissue parenchyma or the reticuloendothelial system. Although mechanisms for iron handling are highly regulated, treatment with intravenous iron has the potential to either bypass or overwhelm these safety systems. It is therefore important that treatment be administered safely and its results closely monitored.

Iron Overload

Several complications may occur with inattentive intravenous iron use. Iron overload may ensue if iron is administered indiscriminately and serum ferritin is allowed to rise to very high levels. Parenchymal damage to organ systems similar to what is seen in hereditary hemochromatosis could potentially result.[121] It is unlikely that iron overload to this degree will occur in hemodialysis patients as a result of iron treatment, given that rHuEPO gains its efficacy from consumption of iron stores. However, a recent study using a superconducting quantum interference device (SQUID), found excess iron in the liver of 70% of hemodialysis patients.[122] What the quantitative and pathological significance of this finding is remain undetermined.

Risk of Infection

The relationship of iron treatment to the risk of infection is incompletely understood. Bacteria and other organisms are reliant on the availability of iron for a variety of metabolic processes, including virulence, and several studies in animals have clearly demonstrated that iron administration can promote infections [123] [124] [125] (as has, by inference, the historical experience with deferoxamine and precipitation of bacterial and fungal infections in dialysis patients). [126] [127] Dialysis patients, at baseline, have a high risk of infection by virtue of the underlying immunosuppressive state of their disease and the nature of the appliances and repetitive procedures required to perform either hemodialysis or peritoneal dialysis.[128] The role of iron exposure as a compounding risk factor in this complicated setting is both unclear and difficult to study, but some studies have shown an association between the serum ferritin concentration and the risk of infection. Kessler and colleagues found that the rate of infection was greatly increased when serum ferritin was over 1000ng/mL.[129] In a subsequent analysis, this group found that a serum ferritin level higher than 500ng/mL was a risk factor for infection.[130] Similarly, Tielemans and associates found an increased risk when serum ferritin was greater than 500ng/mL.[131] The relationship between high serum ferritin and risk of infection in these studies might indicate that high levels of iron storage are causally linked to the risk of infection. However, a confounding issue is the behavior of serum ferritin as a potent acute-phase reactant[102]; the high serum ferritin concentrations may simply reflect the presence of or predisposition for infection rather than indicating causality. Of note, in a well-designed prospective multicenter European study, no relationship was found between serum ferritin and the risk of infection.[128] Further research in this area is clearly needed.

Another path for investigating the relationship between iron and infection in hemodialysis patients is via analysis of supplemental iron administration. Canziani and co-workers found an increased risk of infection in patients who received a greater number of intravenous iron doses.[132] In an elegant series of experiments, Parkkinen and colleagues found that iron sucrose injection resulted in free iron in the circulation, thereby creating conditions that strongly supported the growth of Staphylococcus epidermidis in vitro.[133] Jean and co-workers found that the cumulative intravenous iron dose was a predictor of risk for bacteremia in hemodialysis patients with tunneled catheters.[134] In contrast, Hoen and associates recently analyzed data from a large multicenter study and found no association between intravenous iron dosing and risk for bacteremia.[135] Given the conflicting results in the present literature, it is difficult to reach evidenced-based conclusions that could aid in practice. Until further data become available, the risk of infection should be considered in clinical decision making related to intravenous iron administration. It would seem reasonable, based on current knowledge, to avoid intravenous iron treatment during episodes of acute infection.

Oxidative Stress

A second potential, but poorly understood issue in the long-term safety of repetitive iron infusion is related to iron-mediated oxidative injury to tissues or vessels. As noted, under certain conditions, iron causes the oxidation of biomolecules, including proteins, DNA, and lipids.[136] Zager and colleagues found that iron dextran, oligosaccharide, gluconate, and sucrose all led to substantial lipid peroxidation in vitro. In this study, cellular toxicity occurred more with nondextran forms of iron.[137] The capacity for intravenously administered iron to catalyze “free iron” reactions may depend on whether—and to what degree—iron is bound to its drug vehicle: iron bound in drugs may be less available for oxidative interaction with cells than free circulating iron is. If the affinity of iron for its drug vehicle is low, free (labile) iron could potentially appear in serum or plasma; and recent studies indicate that this does in fact occur with intravenous iron treatment. Parkkinen and colleagues have reported this finding with therapeutic doses of iron sucrose. After the injection of 100 mg iron sucrose, 7 of 12 subjects had free iron detectable in plasma.[133] Similarly, Agarwal compared iron drugs, and found an even greater degree of iron release from ferric gluconate than iron sucrose.[138] Furthermore, Agarwal and co-workers studied patients with chronic kidney disease and found that intravenous iron injection led to increased oxidative stress, enzymuria, and proteinuria; all occurring shortly after injection.[139] Rooyakkers and colleagues associated free iron release with oxidative stress, finding that injection of iron sucrose into healthy volunteers caused release of free iron into the circulation, a significant reduction in flow-mediated vascular dilatation, and generation of superoxide radicals.[140]

The clinical relevance of oxidative stress with intravenous iron treatment is unclear. Studies such as those described above suggest strongly that (1) intravenous iron probably does release some iron directly into the circulation, (2) the amount of iron immediately released may often overwhelm the ability of transferrin to buffer the iron, resulting in free, labile iron in circulation, (3) this free, labile iron probably increases oxidative stress. What is less clear is the quantitative importance of the induced oxidative stress. Humans are constantly and continuously experiencing oxidative stress due to endogenous metabolism and exogenous environmental exposures. Cellular antioxidant systems usually prevent injury by neutralizing reactive oxygen species. Surges in oxidative stress that overwhelm the antioxidant systems can result in oxidative tissue injury. It is unknown whether the oxidative stress occurring with intravenous iron treatment is sufficient in magnitude and duration to lead to injury. However, because of the importance of oxidative stress in relation to highly relevant pathological processes such as atherosclerosis, further research on the contribution of intravenous iron is essential.

The potential role of iron in accelerating cardiovascular disease has been proposed on the basis of the ability of iron to cause lipid oxidation and lipid peroxidation in vessel walls. This link was first proposed by Sullivan in 1981, who suggested that iron deficiency might provide a measure of protection against atherosclerotic disease.[141] Because of the high prevalence of cardiac disease in patients with kidney disease[142] and the frequent use of iron supplementation, any relationship between the two is of potential clinical relevance. Unfortunately, few published reports have addressed this subject specifically in patients with kidney failure, so knowledge must be extrapolated from studies in other populations. In one such study, Salonen and co-workers analyzed the risk for myocardial infarction in 1931 middle-aged Finnish men. They found that a serum ferritin level higher than 200ng/mL was an independent risk factor for cardiac disease, with an odds ratio of 2.2.[143] In contrast, Magnusson and associates studied over 2000 men and women and found no association between serum ferritin and cardiac risk.[144] Indeed, results from the literature have been mixed, with more negative than positive studies. [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] Given the complexity of this subject and its implications for long-standing dual therapy with iron and rHuEPO, further research in this area is needed.

DELAYED OR DIMINISHED RESPONSE TO rHuEPO TREATMENT

In the 1989 multicenter phase III trial of rHuEPO, 97% of patients responded to intravenous treatment with an increase in hematocrit to a target of 35% ± 3% within 12 weeks of initiation of therapy; starting doses were either 150 or 300U/kg per treatment, with subsequent dose reduction to 75U/kg per treatment titrated to maintain a stable target value. The median maintenance dose of rHuEPO was 75U/kg (225U/kg/wk, range of 37.5 to 1575U/kg/wk).[18] As a result of this trial and a literature review appearing in the evidence-based U.S. K/DOQI anemia guidelines in 1997 and 2001, a threshold definition of rHuEPO resistance was proposed—namely, an inability to reach the target hematocrit over a period of 4 to 6 months given adequate iron stores at a dose of 450U/kg/wk administered intravenously (300U/kg/wk subcutaneously) or failure to maintain the hematocrit subsequently at that dose. [19] [56]European guidelines[20] reported lower limits, 300U/kg/wk, as most patients received rHuEPO by subcutaneous injection during the period these guidelines were being characterized (see later section on Anti-rHuEPO Antibodies).

This definition now merits revisiting, given present patterns of utilization. A large fraction of rHuEPO resistance is due to reversible processes (resolving infection, reticuloendothelial blockade from other treatable sources, iron deficiency, or successful resolution of a secondary illness [153] [154]). When dose-per-administration is examined in the United States, however, the upper 20% of patients consume a disproportionate amount of hormone compared to the lower 80%, and, in addition, a nearly thirty fold difference in dose exists between 1st and 99th percentiles of dose per administration. Fully 20% of patients receive an rHuEPO equivalent of 30,000IU/week, or 428U/kg/wk in a patient of 70 kg.[22] Taken together with clinical experience gleaned over the 18 years since this agent's release, these demographics obligate broader guidelines for evaluation of persistent inability to reach or maintain desired hemoglobin. Evaluation for one or more of the issues outlined later[22] should be undertaken if (1) hemoglobin is inappropriately low for the magnitude of rHuEPO dose administered, (2) if an increase in rHuEPO dose is required to maintain stable hemoglobin, (3) if a decrease in hemoglobin at a constant dose of EPO is noted, or (4) if a dose of greater than 500U/kg/wk fails to increase hemoglobin to more than 11.0 g. The realities of new payment regulations in the United States may result in less satisfactory treatment for patients manifesting profound resistance to rHuEPO (i.e., those requiring greater than 500,000u rHuEPO per month, or 35,700–38,500u/dialysis in a month of either 14 or 13 sessions), as Medicare has recently established an upper monthly dose limit for hormone reimbursement.

Iron Deficiency

The most frequently encountered source of an inadequate response to rHuEPO is iron deficiency,[19] which evolves as a consequence of either iron loss, iron consumption by the growing erythron in an appropriate response to rHuEPO treatment, [19] [60] or of lesser importance, inadequate gastrointestinal absorption of oral iron. Proper detection of iron deficiency, particularly in the setting of hemodialysis, requires appreciation of potential losses occurring at the patient's interface with the dialysis machine, as well as processes intrinsic to the patient. In patients during the predialytic stages of CKD or in those receiving peritoneal dialysis, the aforementioned issues are relevant to a far lesser degree because of the absence of extracorporeal circulation and repetitive systemic anticoagulation. Blood loss associated with the dialysis procedure may be phlebotomy related as a result of inadequate blood return from the dialyzers or tubing, suboptimal heparinization, hematoma formation from poor access cannulation, loss of dialysis equipment from insufficient anticoagulation, or excessive access bleeding after dialysis. Iron loss from other sources may also be inferred clinically from an inability to raise iron stores in the face of repeated courses of therapy or from a progressive increase in rHuEPO requirements. Of importance, several forms of iron loss may occur simultaneously. In patients who have adequate iron stores as defined by appropriate transferrin saturation and serum ferritin concentrations, however, other contributors to treatment resistance are noteworthy and discussed in the following paragraphs.

Secondary Hyperparathyroidism

Several studies, most from the pre-rHuEPO era, have investigated whether PTH exerts a direct inhibitory effect on erythroid proliferation, with indeterminate conclusions. [155] [156] [157] [158] Experience with rHuEPO treatment since its availability, however, suggests a more complex relationship between PTH excess and response to rHuEPO. A correlation exists between rHuEPO requirements and the degree of marrow fibrosis, osteoclastic and eroded surfaces seen on bone biopsy specimens, and PTH levels.[159] This correlation has been reflected also in the transnational analysis of medical practices in the Dialysis Outcomes and Practice Patterns Study (DOPPS), which has demonstrated a relationship between attaining a hemoglobin concentration of ≥ 11.0 g/dL and local practices related to the treatment of high-turnover bone disease; including management of PTH excess and maintenance of eucalcemia (curiously, despite these findings, an increased serum phosphorus was also independently associated with better outcome).[160] Parathyroidectomy or acceleration of rHuEPO treatment (or both) often overcomes this particular block to an adequate response. [19] [20] [161] [162] [163] [164] Given the frequency of iron deficiency, inflammatory insults, and the confounding effects of other subtle causes of a poor response, however, hyperparathyroidism per se must remain a modest contributor to this phenomenon.[165] The effect of non-aluminum-related low-turnover bone disease on responsiveness to rHuEPO is unclear, although one finding suggests that efficacy might be enhanced.[166]

One report suggests a possible role for vitamin D in improving erythropoiesis apart from its effect on PTH levels or serum calcium.[167] The effects of vitamin D as a growth factor in enhancing the response to rHuEPO, apart from effects on PTH and marrow fibrosis, require further investigation. Overall, effective management of high-turnover disease, whether by surgical or biochemical intervention, [160] [168] may have a beneficial effect on the efficacy of rHuEPO treatment.

Aluminum Toxicity

Aluminum toxicity has been seen with decreasing frequency because of major improvements in water purification, widespread application of Association for the Advancement of Medical Instrumentation (AAMI) standards, diminishing use of aluminum-containing phosphate binders, and the availability of non-aluminum-containing agents. Mechanisms for this disorder have been ascribed variably to interference with enzymatic insertion of iron into the heme moiety at closure of the tetrapyrrole ring (or with heme synthesis itself) and competition between aluminum and iron for binding to transferrin before substrate delivery to erythropoietic elements. [169] [170] [171] Increasing rHuEPO dosing has in general proved effective in overcoming initial disruptions in erythropoiesis, [19] [172] [173] as has aluminum exclusion or, when necessary, deferoxamine treatment of bone or central nervous system disease. The hope that rHuEPO treatment might function as a physiologic probe to uncover subclinical aluminum intoxication has not been realized.

Hemoglobinopathies and Hemolytic Anemia

The original promise of replacement therapy, particularly for sickle cell disease, has remained unfulfilled. [174] [175] [176] The initial high-dose therapy was approached optimistically in the hope of increasing fetal hemoglobin synthesis, which has not been seen as a common response to treatment—nor, however, has the induction of hyperhemolytic states, which was also an initial concern in the treatment of these patients.[174] Increasing rHuEPO requirements have been reported in conjunction with induction of slow hemolysis as a result of chloramine excess, [177] [178] responding to its removal with appropriate carbon treatment of city water, and anti-Nform antibody production after subclinical formaldehyde exposure.[179] Hemolysis related to lipid peroxidation manifested as resistance to rHuEPO has recently raised the more general issue of the role of oxidative stress as a modulator of the response to rHuEPO and the role of anemia in general in patients with ESRD.[180]

Folate and Vitamin B12Deficiency

The absence of essential cofactors for hemoglobin synthesis is an impediment to an optimal response to rHuEPO. Though a less likely source of resistance to rHuEPO, particularly in patients receiving appropriate vitamin supplementation or ingesting a reasonable diet, an unexplained poor response should prompt an evaluation of the availability of sufficient cofactor. [181] [182] [183]

Multiple Myeloma

B cell dyscrasias have shown a variable erythropoietic response to therapy with rHuEPO over a wide range of doses. [184] [185] [186] Although relapse and lesion transformation have been reported in both dialysis and nondialysis patients with multiple myeloma managed with cytokine therapy, [184] [187] [188] they are rare, and the use of rHuEPO is not contraindicated in patients with renal disease that is myeloma related.[19]

Inflammation

Extensive experience over the past decade in the direct patient care setting has demonstrated the critical impact of inflammation on response to rHuEPO[189] and has necessitated vigilance in detecting the often minor insults that may serve as root causes of resistance to treatment, in addition to obvious infections, malignancies, and connective tissue disorders. Concomitantly, an extensive literature has also convincingly demonstrated that an inflammatory state chronically underlies the vascular disease and catabolic processes attendant on ESRD, [189] [190] [191] [192] [193] a process in which the dialysis procedure and its related hardware also actively participate. [194] [195] [196] [197] [198] It appears certain that resistance to rHuEPO—and possibly a component of the anemia of CKD as well—is a manifestation of both acute, intermittent, and chronic, continuous inflammatory dyscrasias.

In states of active inflammation (such as infectious processes, surgical insults, and malignancies), iron metabolism is directly altered, and access to iron from the reticuloendothelial system by hematopoietic cells is blocked as a result of enhanced iron uptake by activated macrophages.[199] Ferritin synthesis increases, and gastrointestinal absorption of iron decreases. In addition to reticuloendothelial blockade, a variety of interactions between cytokines and marrow elements can impair the response to rHuEPO. On the basis of experimental evidence in both animals and humans, [200] [201] [202] [203] [204] the presence of sufficient quantities of several proinflammatory cytokines at the marrow level, particularly tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) or IL-6, and interferon-γ (IFN-γ), are thought to impair the growth of erythroid progenitor cells, decrease the local response to erythropoietin, and increase IFN production—a hypothesized mechanism for resistance to rHuEPO in this setting.[199] Of equal or perhaps greater importance is that these mediators may represent a linkage between inflammation, poor response to rHuEPO, and the larger syndrome of malnutrition, wasting, and increased risk of mortality seen in dialysis patients. [192] [193] In this regard, Barany and colleagues[190] and Gunnell and associates[205] have demonstrated clear associations between hypoalbuminemia, elevations in C-reactive protein, and an elevated rHuEPO dose, thus suggesting that these convergent pathogenic processes are potentially associated with poor outcomes.

Carnitine Deficiency

L-Carnitine is an essential cofactor for transmitochondrial transport of fatty acids for oxidation, and it is depleted by hemodialysis.[206] A role for carnitine in maintaining erythrocyte membrane integrity, improving deformability, and thereby increasing red cell survival has been postulated. Data accrued over the past several years (including a meta-analysis reviewing 18 randomized controlled trials[207]) have shown modest efficacy of L-carnitine therapy in improving red cell osmotic fragility [208] [209] and erythrocyte survival time[210] and either raising hemoglobin levels or reducing rHuEPO requirements [207] [208] [209] [210] for management of anemia. Variable benefit has been shown for dyslipidemia or improvement in any specific abnormal lipid fraction. [207] [211] Despite the advent of this literature, the evidence basis for the efficacy of carnitine supplementation, particularly randomized controlled trials, is at best modest.[22] Regulatory requirements for drug reimbursement in the United States permit L-carnitine use only for rHuEPO-resistant anemia without other apparent cause and for refractory intradialytic hypotension.[212]

Angiotensin-Converting Enzyme Inhibition

A relationship between treatment with angiotensin-converting enzyme inhibitors and decreasing hemoglobin levels has been known for many years from observations drawn from the treatment of both post-transplant erythrocytosis[213] and CKD. Since the advent of rHuEPO treatment, a variety of reports have offered divided opinions regarding whether these drugs impede the response to treatment (yes [214] [215] [216] [217]; indeterminate[218]; no[219] [220] [221]; in a series of retrospective and prospective crossover studies). LeMeur and colleagues[214] have shown that plasma levels of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a physiologic inhibitor of erythropoiesis that is degraded in vivo by angiotensin-converting enzyme, are elevated in patients with impaired clearance and those with ESRD. Treatment with angiotensin-converting enzyme inhibitors results in increases in AcSDKP in both populations, more so in dialysis patients. In these individuals, the weekly rHuEPO dose correlated with AcSDKP levels, thus suggesting its possible role as an inhibitor of erythropoiesis. A recent report has suggested a possible role for angiotensin-converting enzyme inhibition-mediated diminution in free testosterone as a potential etiology for this phenomenon in males.[215]

Effect of Delivered Dialysis Dose and Membrane

A few reports have previously suggested that an improved response to rHuEPO is associated with a higher dialysis dose, use of biocompatible membranes, [222] [223] or membranes with specific antioxidant properties.[224] The biologic basis for the former observations remains uncertain at present, inasmuch as patients in the most aggressively dialyzed cohort ever reported (average Kt/V of 1.67) do not augment their hematocrit beyond an average of 28.1% without rHuEPO.[225] Additionally, it is unclear whether the improvements published are related to the delivered dose or membrane choice[226] (although one study utilizing vitamin E-modified membrane experience significant improvement in hemoglobin[224]). The discrete effects of intermittent dialysis and the choice of membrane on response to rHuEPO therefore remain inconclusive. Several reports of daily therapies, whether nocturnal [227] [228] or short daily dialysis, [228] [229] [230] [231] [232] however, have revealed no consistent effect on response to rHuEPO (improved response with increased hemoglobin [227] [228] [231]; modest improvement to no change [229] [230] [232]). As these therapies gain wider acceptance, the relationship between progressive increases in small- and middle-molecule clearance and responsiveness to rHuEPO will gain clearer focus.[233]

Anti-rHuEPO Antibodies

Though reported only three times from the availability of rHuEPO until 1998, from 1998 to 2001 Casadevall and colleagues noted 21 patients [234] [235] in whom pure red cell aplasia (PRCA) developed in the setting of rHuEPO treatment. These patients possessed antibody that neutralized rHuEPO and inhibited erythroid colony formation from normal marrow. Immunosuppressive treatment or discontinuation of rHuEPO treatment resulted in the disappearance of antibody in the large majority of reported cases. In these reports, 19 patients were treated with epoetin alfa and one with epoetin beta. To date over 250 such cases have been reported worldwide, almost exclusively patients with CKD receiving subcutaneous Eprex®, a form of epoetin alfa only available outside the United States.[236] Through a collaboration of various governments, scientific groups, and pharmaceutical manufacturers, this epidemic has been well characterized and its likely cause elucidated.[237] After a change in the formulation of this product it was found that leachates from uncoated rubber syringe stoppers were present and may have caused the immunogenicity resulting in PRCA.[238] A switch to fluoro-resin coated stoppers coincided with a rapid decline in new cases of PRCA. Recovery has been reported following immunosuppressive therapy, including cyclosporin [239] [240] and renal transplantation.[241]

Individual Patient Marrow Sensitivity to rHuEPO

After the initial availability of rHuEPO in the United States, Uehlinger and co-authors described a quantitative method of assessing individual responsiveness to treatment.[242] Although such an expression has not proved to be a stable index of responsiveness to therapy on a large scale over the ensuing decade, it is increasingly apparent that wide biologic variability in response exists among patients who can attain appropriate target hemoglobin levels, assuming the presence of adequate iron stores, and that individual patients may have repetitive waxing and waning of responsiveness in various clinical settings. A recent retrospective analysis from a large, stable dialysis population in Seattle[153] revealed that most patients exhibiting resistance to rHuEPO (i.e., those who required more than 500U/kg/wk rHuEPO or failed to achieve a hematocrit >30%) over a fixed interval did so reversibly when the resistance was precipitated by treatable inflammatory lesions, infections, iron deficiency, or ultimately discovered causes. Additionally, many of the patients who were “resistant” by virtue of requiring doses higher than 500U/kg/wk did in fact achieve the target hematocrit. Of note, Brier and Aronoff[243] and Lacson and colleagues[154] alluded to similar variability in the “normal” response, thus suggesting that prior regulatory efforts to confine rHuEPO reimbursement to a narrow range of hemoglobin levels (11 to 12 g/dL) would be physiologically unachievable due to wide variability in normal responses. Appreciation of this reality has, to some degree, resulted in recent policy changes and newer U.S. payment guidelines through which these goals potentially can gain routine attainment.[244]

THERAPEUTIC GOALS AND BENEFITS: TARGET HEMOGLOBIN ISSUES

Current medical practice regarding target hemoglobin levels in patients with CKD is derived from the National Kidney Foundation K/DOQI clinical practice guidelines, which were first published in 1997[56] and most recently updated in 2006.[22] After an exhaustive review of the literature, the current work group determined the target hemoglobin concentration to be more than 11.0, with lower levels associated with adverse outcomes. An upper limit of 13.0 g/dL was based on the lack of sufficient evidence to support the benefits of routine maintenance of patients at higher hemoglobin levels. Similar efforts in Canada resulted in recommendations for a target hemoglobin concentration of 10.5 to 11.5 g/dL,[245] whereas European Working Party best-practice guidelines, including its most recent iteration in 2004, suggest that hemoglobin also should be maintained above 11 g/dL, with individualization to optimize outcomes [20] [23] (of note is that the latter recommendations also specify a population risk for hemoglobin concentrations > 12.0,[23] namely, patients with severe cardiac disease and New York Heart Association Class III and above).

From an organ system perspective, one may define the optimal hemoglobin concentration as the level that maximizes oxygen delivery to body tissues. Of additional importance are the clinical consequences and manifestations of that level, as well as adverse consequences, if any. Considerable debate regarding the most appropriate target hemoglobin level in this context has taken place since development of the various treatment guidelines, with many opinions being published, generally in the form of editorials or literature reviews. [246] [247] [248] [249] [250] [251] [252] [253] [254] [255] In addition, an increasing body of literature has been published in which this issue has been addressed, with a focus on the benefits and risks of increasing hemoglobin toward or up to normal levels in patients with CKD, the former most recently including the beneficial effects of hemoglobin normalization on immune function, particularly delayed-type hypersensitivity.[256]

Mortality

The relationship between hemoglobin concentration and mortality has been reported in several studies, but variations in both study populations and the degree of study design rigor make it difficult to draw “generalizable” conclusions. [59] [257] [258] [259] [260] Interest in this area was stimulated by studies suggesting that the hemoglobin concentration was an independent predictor of mortality in hemodialysis patients.[261] Cross-sectional analysis of a large administrative database from a national dialysis chain found increased mortality (relative risk [RR], 1.45) when the hematocrit was 35% to 40% as opposed to the reference range of 30% to 35%.[257] Although this study included adjustments for case mix and certain laboratory values, the very low correlation coefficient makes an association between hematocrit level and survival questionable. A larger cross-sectional study was published by investigators using administrative data from the Health Care Financing Administration (HCFA).[258] When compared with patients who had a hematocrit of 30% to 33%, those with a hematocrit of 33% to 36% had a significantly decreased likelihood of death (RR, 0.9). No mortality benefit was found for patients with a hematocrit greater than 36%, although the number of patients in this category was small. A follow-up study from the same group, with a larger number of patients in the hematocrit range of 36% to 39%, found no survival benefit for this group.[259] A final, nonrandomized clinical trial from Spain reported no deaths over a 6-month period in a group of hemodialysis patients whose hematocrit was raised from a baseline mean of 31% to a mean of 38.5%.[260] A recent systematic literature review suggests that the relationship of hemoglobin and mortality is not strongly supported by published evidence.[262]

The only randomized, controlled, adequately powered trial of the impact of normalization of hemoglobin on survival was carried out in a subset of hemodialysis patients with cardiac disease, defined as ischemic heart disease or congestive heart failure.[59] Patients were randomized to a hematocrit of 30% ± 3% or 42% ± 3%. The planned duration of the study was 3 years after enrollment of the last patient. After 29 months, at the time of the third interim data analysis, higher mortality was observed in the higher hematocrit group, and although this higher mortality was not significantly different statistically from the mortality in the lower hematocrit group, the independent safety monitoring committee recommended halting the study. A total of 1233 patients were included in the intent-to-treat analysis, which showed a relative risk of death or first myocardial infarction of 1.3 for the higher versus the lower hematocrit group, although this finding did not reach statistical significance. Of note, however, was a decrease in mortality rate at higher hematocrit in both hematocrit groups when a cross-sectional post hoc analysis of mortality based on the average achieved hematocrit was performed—a finding that could potentially be confounded by survivor effects. Interpretation of this study is further complicated by lower values for Kt/V and more frequent use of intravenous iron in the higher hematocrit group. As pointed out by Macdougall and Ritz,[263] this study had many issues making it difficult to understand the implications of its findings, including the enrollment of only “high-risk” cardiac patients, lack of correlation between achieved hematocrit and mortality (survivor effect), the use of predialysis hematocrit values, the use of hematocrit rather than hemoglobin concentration, and the fact that the excess mortality seen was not related to cardiovascular causes.

Hospitalization

Assessment of the relationship between hematocrit level and hospitalization has been hampered by the lack of sufficient data on other patient characteristics that may influence this complication. In an analysis of a large administrative database[264] in which a Cox proportional hazards method was used to account for differences in patient characteristics, patients in the 33% to 36% hematocrit category had a lower risk of hospitalization than did patients with lower hematocrit levels. It is of note that patients with a hematocrit less than 30% had a 14% to 30% increased risk of hospitalization. In a subsequent study using more recent data,[259] hospitalization rates were 16% to 22% lower, depending on cause, in patients with hematocrit values greater than 36% than in those with lower hematocrit values. A study from Spain[260] reported a 58% reduction in the total number of hospitalizations and a 69% reduction in length of stay in patients after normalization of the hematocrit. It is unclear whether these results from observational studies represent a causal relationship between low hematocrit and increased risk of hospitalization or simply whether a low hematocrit indicates sicker patients at increased risk.

Brain and Cognitive Function

Studies in dogs have documented that the optimal hematocrit for maximizing body oxygen consumption is one in the normal range. [265] [266] Similar findings have been reported in normal volunteers subjected to hemodilution.[267]Partial correction of anemia has been shown to improve brain electrophysiology, as measured by event-related electrophysiology. [268] [269] [270] Similar improvements in cognitive function have been found with partial correction of anemia as well; such improvements were identified with instruments that measure visual, conceptual, and vasomotor tracking, auditory-verbal learning, symbol-digit modality, and trail making, among many others. [271] [272] [273]More recent studies have shown that normalization of the hematocrit leads to even greater improvement in objective measures of brain function, as determined by electrophysiologic techniques.[274] Twenty chronic hemodialysis patients were studied by electroencephalographic frequency analysis before and after correction of anemia from a mean hematocrit of 31.6% to a mean hematocrit of 42.8%. Significant improvement in electrophysiologic parameters was seen at the higher hematocrit, and a significant correlation was observed between the incremental improvement in these parameters and the rise in hematocrit. Additional research on sleep disorders in patients with ESRD, the SLEEPO study, demonstrated significant improvements in sleep patterns and daytime sleepiness when the hematocrit was normalized.[275] The mechanism by which brain function improves with normalization of the hematocrit is unknown, but it may be related to optimization of oxygen delivery to the brain and metabolism. [276] [277] In seven patients with ESRD, full correction of anemia led to an increased oxygen supply to the brain and increased oxygen extraction by brain tissue.[276] In an additional study from Japan, five hemodialysis patients underwent positron emission tomography before and after normalization of the hematocrit. A minimal hematocrit of 35% was found to be necessary to maximize oxygen delivery and brain metabolism.[277] Finally, it should be noted that all the studies described used rHuEPO to increase the hemoglobin concentration. It is of note that erythropoietin is able to cross the blood-brain barrier in rats and ameliorate the extent of brain injury after a variety of insults.[278] Such studies raise the question of whether the improvements in brain and cognitive function seen after improvement and normalization of hemoglobin levels in patients with ESRD are related entirely to its rise, or may in part reflect a direct effect of rHuEPO.

Quality of Life/Exercise Capacity

Considerable evidence demonstrates that partial correc-tion of anemia improves the quality of life of patients with ESRD. [279] [280] [281] [282] More recent studies have shown that normalization of hemoglobin improves the quality of life to an even greater extent. [59] [260] [283] [284] In cardiac patients enrolled in the normalization of hematocrit study,[59] quality of life was assessed by using the Medical Outcomes Study Short-Form Health Survey[285]; as the hematocrit increased, quality of life improved, although few details of the analysis are provided. The Spanish study used the Sickness Impact Profile (SIP) and the Karnofsky Scale in patients before and after normalization of the hematocrit.[260] Highly significant improvement in scores on the SIP and the Karnofsky scale was documented, although the generalizability of these findings could be questioned because patients were excluded from the study if they were diabetic, were older than 65 years, or had a variety of common comorbidities (e.g., severe hypertension, stroke, ischemic heart disease). A prospective, randomized, double-blind crossover study in 14 hemodialysis patients assessed the benefits of full reversal of anemia in stable hemodialysis patients.[283] The total score and psychosocial dimension score were significantly better when the hemoglobin was normalized. Similar findings were reported by Painter and colleagues, who found an improvement in exercise capacity when normalization of hematocrit was combined with exercise training.[284] The latter, however, remained below normal, thus suggesting that the poor exercise capacity in dialysis patients cannot be fully explained by either anemia or deconditioning. These results confirm earlier findings by other investigators [285] [286] [287] and implicate a role for uremia per se or local abnormalities in electrolyte metabolism related to uremia in this clinical abnormality. It is known that Na+,K+-ATPase activity is impaired in uremic rats. [288] [289] [290] Erythropoietin has also been shown to enhance the activity of this enzyme.[291] It is possible that increasing the hemoglobin concentration to normal may be responsible for the improved K+ regulation and exercise performance reported by McMahon and colleagues.[287]

Cardiovascular Disease

Although it is generally accepted that anemia is an independent risk factor associated with left ventricular hypertrophy (LVH), left ventricular dilation (LVD), and increased cardiac mortality [292] [293] [294] and that partial correction of anemia is beneficial in these areas, [295] [296] [297] it is less clear whether these adverse outcomes could be further minimized by normalization of hemoglobin. Recent literature reviews have even questioned whether the association between hemoglobin level and mortality in dialysis patients is supported by the available data. A randomized controlled trial from Canada evaluated the impact of normalizing the hemoglobin concentration on the degree of LVH or LVD present at baseline in a group of hemodialysis patients.[298] After 40 weeks, echocardiography revealed no significant regression of LVH or improvement in left ventricular cavity volume in patients with baseline LVD. However, a significant decrease in the development of LVD was observed in patients who had LVH at baseline. These findings suggest that normalization of hemoglobin may prevent increases in LVD in susceptible patients. A smaller study from Germany confirmed that normalization of hemoglobin can lead to preservation of normal left ventricular dimensions or reverse LVH in hemodialysis patients.[299] More recently, a prospective longitudinal study in 23 hemodialysis patients demonstrated regression of LVH and improvement in left ventricular geometry with hemoglobin normalization.[300] Studies in patients with mild to moderate CKD have also shown the hemoglobin level to be an independent and modifiable risk factor for abnormal left ventricular growth.[294] For each 0.5-g/dL decrease in hemoglobin, the risk of abnormal left ventricular growth increased by 32%. In a separate study from Japan in CKD patients not on dialysis, normalization of hematocrit (40%) was more effective than partial correction of anemia (hematocrit of 30%) in leading to regression of LVH.[301] A randomized trial of hemoglobin maintenance in patients with CKD, however, failed to find evidence of a causal relationship between hemoglobin level and left ventricular mass index.[302] Of interest is a study in patients without kidney disease, but with severe congestive heart failure and anemia (hemoglobin <12 g/dL).[303] Raising hemoglobin levels toward the normal range with rHuEPO led to an increase in the left ventricular ejection fraction, a fall in New York Heart Association class, and a decrease in the hospitalization rate. A large epidemiological data base analysis showed an association between cardiovascular disease and the presence of CKD and anemia.[304] Low hemoglobin, even within the normal range was associated with an increased risk for CVD death in people with CKD, but not in those without CKD. This relationship might be particularly important in patients with diabetes.[305]

Kidney Function

When rHuEPO was introduced into practice, a single study in rats raised concern that correction of anemia might lead to an accelerated loss of renal function in CKD patients.[306] Subsequent studies in humans with CKD, however, failed to show any effect of anemia treatment on the rate of progression of renal failure, [307] [308] [309] [310] and these findings were confirmed in a study using the remnant kidney model.[311] A more recent prospective clinical trial suggests that partial correction of anemia with rHuEPO can retard the progression of renal disease, particularly in nondiabetics.[312] Patients with mild to moderate CKD (serum creatinine ranging from 2.0 to 4.0 mg/dL) and a hematocrit less than 30% were randomized to maintain their baseline hematocrit or receive treatment with rHuEPO. The latter group had a baseline average hematocrit of 27.0%, which rose to 32.1% over the course of the study. Other aspects of medical management were identical in the two patient groups. Serum creatinine doubled in 84% of the CKD patients who remained anemic versus only 52% of those whose anemia was treated with rHuEPO. Jungers and colleagues measured the rate of decline of creatinine clearance in patients with CKD maintained anemic (hemoglobin ≈10 g/dL) and compared them with patients whose anemia was treated with rHuEPO (hemoglobin =11.3 g/dL).[313] The latter group of patients had a significantly slower rate of decline in renal function when compared with the former group. Most recently, the RENAAL study (Reduction in Endpoints in Non– Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), a prospective, long-term clinical trial of type 2 diabetics with nephropathy (n = 1513; serum creatinine, 1.9 ± 0.5 mg/dL; albumin/creatinine ratio, 7.1 ± 1.0 mg/g; follow-up, average of 3.4 years), evaluated the baseline hemoglobin concentration as a risk factor for a poor renal outcome. In this analysis, the baseline hemoglobin concentration was independently associated with a poor renal outcome, either time to ESRD or time to the combined end point of ESRD or doubling of serum creatinine from the baseline value. After adjustment for covariates, each quartile (reference hemoglobin >13.8 g/dL) showed an increased risk for a poor outcome when compared with the reference group, thus suggesting that prevention or amelioration of anemia may lessen the risk for progression to ESRD in these patients.[314] A recent randomized controlled trial in 88 patients demonstrated that initiation of anemia treatment in CKD patients with non-severe anemia (hemoglobin 9 to 11.6 g/dL) resulted in a 60% reduction in the risk of ESRD or death.[315]

Blood Rheology/Hemostasis/Oxidative Effects

Data on the potential effects of normalization of hemoglobin on vascular access clotting are limited. (Generic coagulation-related issues related to rHuEPO treatment are reviewed elsewhere in this contribution.) Besarab and associates found a significant increase in vascular access thrombosis, in autologous arteriovenous fistulas as well as synthetic grafts, in patients randomized to a higher hemoglobin concentration.[59] In the Spanish study of hemoglobin normalization, however, no such increase in access clotting was observed.[260] The effects of normalization of hemoglobin on blood rheology and hemostasis have only recently been examined. [316] [317] [318] Thirty-nine patients with normal hematocrit (42%) were studied, but no significant changes in RBC aggregation or deformability were observed during a hemodialysis session. [316] [317] In a study from Sweden, hemostatic parameters (prothrombin complex test, activated partial thromboplastin time, platelet aggregation and retention, von Willebrand factor antigen, antithrombin, protein C, total and free protein S, activated protein C resistance, factor V-Leiden mutation, D-dimers, plasminogen activator inhibitor-1, and prothrombin fragments 1 and 2) were examined in a group of patients with CKD before and after normalization of hemoglobin with rHuEPO.[318] The only statistically significant finding was a transient decrease in total levels of protein S. Finally, complete correction of anemia in hemodialysis patients has been associated with a significant increase in whole-blood antioxidant capacity, indicative of a positive effect on free radical metabolism.[319]

It is clear that the base of evidence to assess the benefits and risks of normalization of hemoglobin adequately in CKD patients is still insufficient. Although considerable data continue to build and suggest that such an approach might lead to improved patient outcomes, the high cost of treatment and the possible complications of therapy have not been thoroughly assessed. At present it seems prudent to base the treatment of most patients on guideline recommendations from the National Kidney Foundation or the Canadian or European guideline groups, given the clear improvement in a wide variety of outcomes with progressive increases in hemoglobin. [19] [20] [21] [22] [23] [56] [245] Individualization of treatment, however, remains the cornerstone of the art of medicine and should be applied to the treatment of anemia so that patients who might benefit from normalization of hemoglobin are so treated. [320] [321] [322] [323]

Since late fall of 2006, three publications, taken together, have stimulated further discussion regarding hemoglobin goals for erythropoietin treatment. All are randomized controlled trials examining the effects of targeting near-normalization to normalization of hemoglobin on a variety of parameters in patients with CKD, not yet on dialysis. The CHOIR[323a] study, performed in the United States, examined the effect of targeting near-normalization of hemoglobin on patients with eGFR between 15-50 mL/min, with patients randomized to target hemoglobin of either 11.3 or 13.5 g/dL. The authors report a statistically significant increase in cardiovascular events, the suggestion of increased progression of kidney disease, and no incremental improvement in quality of life in the high hemoglobin target group. The European CREATE[323b] study examined similar parameters in a smaller patient cohort with eGFR 15-35 mL/min, with patients randomized to target hemoglobin ranges of either 10.5–11.5 or 13-15 g/dL. These authors found no significant effect of normalization of hemoglobin on cardiovascular events (neither reduction nor increase) or eGFR, but significant benefit of higher hemoglobin targets on quality of life. In another European study, ACORD,[323c] change in LVMI was measured in diabetic patients with CKD stages 1-3 (creatinine clearance ≥ 30 mL/min. Patients were randomized to hemoglobin targets of either 10.5–11.5 g/dL, or 13-15 g/dL. In those assigned to the higher hemoglobin target group, there was no improvement in LVMI. No clinically relevant difference in rate of adverse events or difference in rate of deterioration of renal function was noted between groups, and quality of life was significantly improved in the higher hemoglobin group. The sole comparable study addressing these issues in patients actually receiving renal replacement therapy remains Besarab et al[59] from 1998, which has been both detailed and evaluated above. These three recent studies have focused attention again on what constitutes appropriate target range for erythropoietin treatment in the setting of CKD and ESRD, and are now the subject of vigorous analysis, debate, and evaluation.

PHARMACOECONOMIC AND End-Stage Renal Disease PROGRAM-RELATED ISSUES IN rHuEPO TREATMENT

After approval of rHuEPO by the U.S. FDA in 1989, the HCFA (now the Center for Medicare and Medicaid Services [CMS]), an agency in the Department of Health and Human Services, was responsible for developing an appropriate policy for its reimbursement. Several key issues in this regard immediately became apparent and have been addressed in numerous publications, [327] [328] [329] [330] [331] along with additional discussions regarding the pharmacoeconomics of rHuEPO therapy. [332] [333] [334] [335] [336] [337] [338] These issues and their resolution in subsequent policy have had a direct bearing on the day-to-day use of rHuEPO and have shaped standard practice in the correction of anemia.

Several alternative payment approaches are available for the use of any pharmaceutical given during dialysis, including a fixed rate per treatment independent of the dose used, inclusion in the composite rate (the payment that CMS offers as a flat reimbursement for the cost of each dialysis treatment), and payment according to a fee schedule.[325] The initial approach to payment for rHuEPO was a fixed rate per treatment, with $40 paid to dialysis facilities for a dose of 10,000U or less and $70 paid for a dose greater than 10,000U.[324] These payments were to cover the cost of the medication, but not its administration, which according to the CMS was already being addressed by the facility composite rate for dialysis treatments. At that time the list price to wholesalers was stated to be $10 per 1000U.[324] The fixed payment per treatment in this fashion created the possibility of encouraging providers to limit dosing because even a single unit of rHuEPO would be reimbursed at $40. In the first year of Medicare coverage for rHuEPO, Medicare paid $144,000,000 for this therapy to dialysis providers,[336] but hemoglobin levels remained below recommended targets, and lower than expected rHuEPO doses were provided.[326] Providers explained that because Medicare paid only 80% of the allowed charges ($32 or $56, respectively, depending on the dose administered), it did not cover administration costs, and because a slower rise in hemoglobin was medically desirable, they used lower than anticipated doses. Medicare, however, thought that this practice resulted in a large profit margin for providers and that it was this profit margin, not the quality of care that was the primary driver for the providers. This policy was further complicated by the fact that patients had to have a hematocrit less than 30% for reimbursable therapy to be initiated and that no payment would be made if it exceeded 36%. Finally, because self-administration of medications is not reimbursable by Medicare, home dialysis patients had to receive rHuEPO in the physician's office or dialysis center.

Starting in January 1991, this payment policy was changed. Payment was made on a per-unit basis linked to a fee schedule, with an initial approved rate of $11 per 1000U administered.[327] The actual cost of acquisition by providers varied, depending on contractual arrangements with the manufacturer. This policy created conflicting incentives, with overuse encouraged on the one hand under the assumption that acquisition costs were less than reimbursement amounts, whereas the need to avoid excessively high hematocrit levels, which would result in no reimbursement, encouraged underuse. A careful analysis of the effects of the payment change showed that in the 6 months after its implementation, the dose of rHuEPO increased over 14%, the hematocrit increased just 0.2% to 0.3%, and the allowed charges for rHuEPO rose.[327] In addition, patients treated at for-profit facilities had lower rHuEPO doses before the change in policy and higher doses after the change in policy than patients in nonprofit facilities did.[327] These findings illustrate the important influence of payment policy on clinical practice in this area.

Subsequent payment policy decisions again demonstrated their powerful influence on clinical practice with introduction of the initial hematocrit management audit (HMA) system by the CMS in 1996.[328] In response to concerns regarding lack of payment for rHuEPO if the hematocrit exceeded 36% and as an acknowledgment of the biologic variability in hematocrit values among patients, as well as fluctuations in an individual patient over time, the CMS implemented the use of a 3-month rolling average hematocrit exceeding 36.5% as the trigger to deny payment for rHuEPO for the entire month of treatment. The effect of this policy was both predictable and chilling. Providers concerned about lack of payment for rHuEPO began to reduce dosing to be certain that the hematocrit remained within limits. Average doses fell, as did the average hematocrit. The fraction of patients with severe anemia (hematocrit <30%) rose concomitantly.[337] In response to clear evidence of the negative impact of this policy and after considerable input from providers, the policy was changed. The 3-month rolling average hematocrit remained, but a level of 37.5% was set as the upper limit, and unlike the previous policy of withholding payment if the upper limit was exceeded, under the new policy, payment would still be made, but a “post-payment review” could be undertaken at the discretion of the local insurance carrier contracted to pay the claims on behalf of Medicare. The result of this policy revision has been a steady rise in rHuEPO doses and mean hematocrit. Despite this improvement, however, it is clear that significant variability still remains in the hemoglobin levels achieved in dialysis patients,[154] which has been attributed to differences in the target hemoglobin range and perception of the threshold for action, variability in anemia management approaches, and intrapatient variability. [154] [341] [342] More recent changes in payment policy may significantly improve the ability of clinicians to achieve appropriate hemoglobin levels in patients with ESRD.[244] The upper limit of “acceptable” hemoglobin for payment has been extended to 13 g/dL (the new limit suggested in the K/DOQI guidelines[22], as well), and even if this is exceeded the clinician will not be penalized if the EPO dose is adjusted appropriately (decrease of at least 25%), as recommended by NKF-KDOQI guidelines.

Payment policy for pharmaceuticals is best framed in the context of pharmacoeconomics, namely, what are the overall costs and benefits of a particular agent? Such an analysis is often difficult and has been particularly so for rHuEPO.[329] Although the direct costs of acquisition and administration are not difficult to quantify, the “costs” of other benefits and complications of rHuEPO therapy are more challenging to understand. For example, a complete pharmacoeconomic analysis of this hormone would consider the decrease in transfusion requirements and androgens with anemia treatment, improved quality of life, value of the lack of sensitization and delay in kidney transplantation, decrease in hospitalizations, and improved survival (the last of which includes more ongoing costs of dialysis and overall medical care). [333] [334] [335] [336] The costs of parenteral iron, additional antihypertensives, and procedures to clear vascular access clotting must also be considered. When such studies were performed by Powe and colleagues[333] in the early years of experience with rHuEPO, they found that the total cost for treating with rHuEPO versus blood transfusions or androgens was substantial, highly sensitive to the dose of rHuEPO, moderately sensitive to response rates to rHuEPO and reduction in cardiovascular morbidity, and slightly sensitive to transfusion rates, among other factors. When a more rigorous analysis was performed by the same group[334] in which dialysis patients who received rHuEPO were compared with those who did not, they found that rHuEPO treatment was associated with a decrease in readmissions, overall admissions, hospital days, and cost to the hospital, thus suggesting that overall, Medicare may realize substantial savings when anemia is appropriately treated with rHuEPO.

Recent experience has underscored the validity of this assumption. During the 1990s, doses of rHuEPO began to rise, as did average hemoglobin levels. This trend accelerated after the publication of clinical practice guidelines of 1997 and 2001 on the management of anemia in which a target hemoglobin of 11 to 12 g/dL was recommended. [19] [56] An analysis of data from CMS claims files showed that patients with hematocrits ranging from 33% to 36% had lower Medicare-allowable expenditures per month than did those with hematocrits ranging from 30% to 33%.[335] Patients with hematocrits less than 30% had even higher expenditures. These findings suggested that management of anemia with rHuEPO could result in overall cost savings, primarily by decreasing hospitalization rates. These findings were expanded in a more recent cohort of patients.[340] Patients undergoing hemodialysis in 1996 to 1998 were studied and their medical costs evaluated, with a focus on patients with a hematocrit greater than 36%. Patients with a hematocrit greater than 36% had a 16% to 22% lower hospitalization rate than did those in the reference range (hematocrit of 33% to 36%). In addition, expenditures were 8.3% to 8.5% lower in patients in the higher hematocrit group. Whether the lower expenditures were causally related to the higher hematocrit achieved cannot be determined by an epidemiologic study of this nature, but additional studies in this area are certainly warranted.

Total Medicare expenditures for rHuEPO in 2003 exceeded $1.6 billion and have increased by nearly 10% just between 2002 and 2003. Costs for adjunctive therapy with intravenous iron have increased by over 5% over this same period.[341] As alluded to earlier, one approach to lowering the costs of rHuEPO is to administer the drug subcutaneously because of its significant dose-sparing effect in achieving equivalent hemoglobin levels. [19] [56] [245] [345] It has been estimated that this approach alone could save Medicare up to $144 million annually.[343] Of the many barriers to this approach at present, most recently concern has been expressed over the possible appearance of neutralizing antibodies to rHuEPO, which though uncommon, seem to be more likely when subcutaneous rather than intravenous administration is used. [234] [347]

A major driver of current patterns of rHuEPO use is related to the overall structure of the payment system to dialysis facilities for ESRD services, an area of great interest and concern to regulators and providers. [348] [349] [350]Composite rate payment, which began in 1983, was designed to include all nursing services, supplies, equipment, and drugs associated with a single dialysis session.[345] The amount of the payment has been modified only minimally since that time despite numerous technologic changes in the delivery of dialysis care and increasing costs of providing safe and adequate treatment. The composite rate payment does not include, however, payment for certain injectable medications (e.g., rHuEPO, iron, vitamin D), many laboratory tests, and blood and blood products. Recent analyses by the Medicare Payment Advisory Commission (Medpac), an independent federal body established by statute in 1997 to advise Congress on Medicare-related issues, clearly show that the current composite rate payment is inadequate to cover the cost of providing dialysis treatments for most facilities.[346] The financial viability of the facilities thus becomes dependent to a significant extent on the excess revenue generated from injectable drugs, most importantly, rHuEPO, for which acquisition costs are still considerably lower than the current allowable reimbursement rate (although only 80% of the latter is actually paid by Medicare). Medpac found that payment-to-cost ratios for composite rate services for in-center and home dialysis ranged from 0.86 to 1.00, depending on the size of the facility, profit status, and location, thus indicating that at best, facilities were able to break even (large facilities), but smaller, nonprofit, and rural facilities were losing considerable sums based only on the composite rate. When separately billable drugs were included in the analysis, payment-to-cost ratios rose and ranged from 0.97 to 1.07, with the same facility characteristics predictive of the level.[346] As is apparent from this analysis, facilities have an incentive to maximize the use of injectable drugs, including rHuEPO, thereby driving therapy that could preferentially recommend intravenous versus subcutaneous administration and conservative use of parenteral iron, with both approaches leading to higher rHuEPO use for a given target hemoglobin level.

It is of interest that when the payment for dialysis services includes injectable drugs in a bundled or case rate approach, their use decreases because they become a cost rather than a revenue generator (J.D. Dickmeyer, M.D., personal communication, August 2002). Medpac has recommended that such an approach be explored for the Medicare ESRD program, [348] [349] and a study is currently under way to better understand the implications of such an approach. It is clear that the payment system, no matter how it is constructed, has in the past and will in the future drive medical practice.[347] It is there-fore essential to have an ongoing assessment of relevant outcomes of anemia management to ensure that current medical practice remains focused on the highest quality of care for patients.

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